Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

Abstract

Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

“…While the conventional treatment technologies can eliminate intact toxic cyanobacterial cells effectively, these technologies have limited capability for removal of dissolved cyanobacterial toxins, which allows that these reach human populations via drinking water supplies in sufficiently high concentrations to cause adverse effects in the gastrointestinal system (Table 1). Chronic exposures to drinking water contaminated with cyanobacterial compounds, in some instances in combination with other confounding factors, have been associated with an increased incidence of liver cancers or chronic liver damage and diseases, as reviewed and discussed by Svirčev et al [12], and supported by recent findings [18][19][20]. Interestingly, epidemiologic studies have also linked chronic exposures to drinking water contaminated with cyanobacteria and their metabolites to the increased incidence of colorectal or small intestinal cancer in China [21], Portugal [22], and Serbia [12,23], or stomach cancer mortality in China [24].…”

Microcystin‑leucine arginine promotes colorectal cancer cell proliferation by activating the PI3K/Akt/Wnt/β‑catenin pathway

“…In a previous study, MC-LR activated MMP expression and promoted breast cancer cell migration ( 10 ). MC-LR also induced hepatocarcinogenesis in vitro and in nude mice ( 11 ). In addition, MC-LR has been shown to promote prostate epithelial cell proliferation ( 6 ).…”

Effects of Cyanobacterial Toxins on the Human Gastrointestinal Tract and the Mucosal Innate Immune System

“…While conventional treatment technologies can eliminate intact cyanobacterial cells with toxins quite effectively, these technologies have limited capability for removal of dissolved cyanobacterial toxins, which allows them to reach taps in sufficiently high concentrations to cause adverse effects in the gastrointestinal system (Table 1). Chronic exposures to drinking water contaminated with cyanobacterial compounds, in some instances in combination with other confounding factors, have been associated with an increased incidence of liver cancers or chronic liver damage and diseases, as reviewed and discussed by Svircev et al [12], and supported by recent findings [17][18][19]. Interestingly, epidemiologic studies have linked chronic exposures to drinking water contaminated with cyanobacteria and their metabolites also to the increased incidence of colorectal or small intestinal cancer in China, Portugal and Serbia, or stomach cancer mortality in China [12,20,21].…”